Since enzymes are involved in most life processes, it is crucial to gain a detailed understanding of their action. The importance of such an understanding is highlighted by the fact that many diseases can be controlled by developing drugs that block the action of enzymes in crucial biological pathways of pathogens that cause these diseases. Quantifying the analysis of enzyme catalysis can be greatly advanced by computer simulation approaches that correlate enzyme structures with their activity. Here the progress should involve both advances in quantifying the fundamental basis of enzyme catalysis and in developing practical predictive power in studies of diverse classes of enzymes. Thus we propose to continue in advancing the frontiers of this field, while shifting a significant part of ur focus to the the emerging field of enzyme design. The advances on this front should provide a deeper understanding of catalysis, help in controlling what a given enzyme is doing as well as the use of specialized enzymes. We note, however, that the progress in enzyme design has not yet led to designer enzymes that rival native enzymes. Thus, it is clear that the potential of this field can be greatly enhanced by computational approaches that evaluate the activation barriers of the reactions that are being catalyzed. In order to progress in both quantifying enzyme design and in enhancing the general understanding of enzyme catalysis, we propose parallel advances in the following directions: (i) We will validate the reliability of our EVB-based computer-aided enzyme design by reproducing the observed catalytic effects of key designer enzymes. (ii) We will continue to develop more quantitative design concepts as well as fast screening methods. After exploring the predictive power of these approaches, we will use them in collaboration with research groups that are involved in actual enzyme design experiments. (iii) We will continue to advance quantitative computational methods including the paradynamics QM(ai)/MM-FEP approach that should help us to obtain activation free energies of enzymatic reactions by ab initio methods. (iv) We will quantify the relationship between folding and stability and explore th relationship between thermostability and catalysis. (v) We will explore the catalytic effect of directed evolution, trying to elucidate its relationship to natural evolution. (vi) We will conduct studies of several important classes of enzymatic reactions. (vii) We will continue with the systematic examination of different nonelectrostatic catalytic proposals.